For the purpose of treating malignant tumors or viral diseases, various nucleic acid antimetabolites has been developed, and cytarabine, gemcitabine, doxifluridine, azacitidine, decitabine, nelarabine and the like as antitumor agents (anticancer agents), and zalcitabine, lamivudine and the like as antiviral agents are clinically used.
However, even though these nucleic acid antimetabolites exhibit strong in vitro activity, many of the antimetabolites cannot sufficiently exhibit the efficacy inherently possessed by the drugs or need to be administered in large amounts, owing to their susceptibility to in vivo metabolism and excretion. For example, gemcitabine has a strong in vitro cell growth inhibitory activity which is comparable to that of anticancer agents such as paclitaxel or doxorubicin, while in clinical practice, gemcitabine requires a high dose of 1000 mg/m2 of the body surface area per administration. This is believed to be because the in vivo bioavailability is decreased as the amino group at the 4-position of the base is metabolized/deactivated by a cytidine deaminase, which is a 2′-deoxycytidine metabolizing enzyme (Non-Patent Document 1).
In some cases, binding of a drug to a polymer results in an improvement in the pharmacokinetics in vivo, and thus leading to an enhancement of the therapeutic effect. Non-Patent Document 2 describes a high molecular weight derivative in which a polyglutamic acid having an average molecular weight of about 30,000 is conjugated with cytarabine. However, such high molecular weight derivatives of drugs often induce hypersensitivity due to immune responses, and in that cases, the high molecular weight derivatives as a drug cannot be administered repeatedly.
Patent Document 1 describes a high molecular weight derivative in which a cytidine derivative is bound to a polyethylene glycol, and Non-Patent Document 3 describes a high molecular weight derivative in which both ends of the chain of a polyethylene glycol are substituted with aspartic acid in a branched form, and cytarabine is bound thereto. Furthermore, Patent Document 5 describes a high molecular weight derivative having a structure in which the ends of a polyethylene glycol chain are branched by using amino acids, and each of the branches releases drug after being subjected to a benzyl elimination reaction. However, for all of these high molecular weight derivatives, the rate of hydrolysis in the plasma is several tens of hours at the most, that is, the rate is not so much slowed, and the high molecular weight derivatives themselves do remain in vivo for a long time and do not release the included compounds over a long time. Furthermore, since these high molecular weight derivatives have large differences between the rate of hydrolysis in phosphate buffered physiological saline (PBS) and the rate of hydrolysis in the blood plasma, and the hydrolysis reaction depends largely on the enzymes in vivo, it is possible that the therapeutic effects in the clinical practice may be greatly affected by the individual differences of patients.
Patent Document 2 states that molecules in which a drug is bound to a block type polymer having a polyethylene glycol condensed with polyaspartic acid, form micelles and serve as a medicine. Furthermore, Patent Document 3 describes a high molecular weight molecule in which an anticancerous substance is bound to a carboxyl group in the glutamic acid side chain of a block type polymer having a polyethylene glycol condensed with polyglutamic acid. However, there is no description with regard to these high molecular weight derivatives using a nucleic acid antimetabolite as the drug binding thereto.
In addition, Patent Document 4 states that a water-soluble high molecular weight derivative in which a carboxyl group of a polymer of polyethylene glycol and polycarboxylic acid is linked to a phenolic hydroxyl group of a phenolic camptothecin by ester condensation, is suitable for cancer chemotherapy. However, the mode of binding of the drug in this molecule is an ester formed by phenol group bound to a carboxyl group, and this is not an ester formed by a primary alcohol or secondary alcohol bound to a carboxyl group. Also, no description is provided with regard to this high molecular weight derivative using a nucleic acid antimetabolite as the drug binding thereto.
Patent Document 1: Japanese Patent Application Laid-open Publication (Kohyo) No. 2003-524028
Patent Document 2: Japanese Patent No. 2694923
Patent Document 3: Japanese Patent Application Laid-open Publication (Kokai) No. 5-955
Patent Document 4: WO 2004/039869
Patent Document 5: Japanese Patent Application Laid-open Publication (Kohyo) No. 2004-532289
Non-Patent Document 1: Cancer Science, Japanese Cancer Association, Vol. 95, pp. 105-111 (2004)
Non-Patent Document 2: Cancer Research, American Association for Cancer Research, Vol. 44, pp. 25-30 (1984)
Non-Patent Document 3: Journal of Controlled Release, Elsevier, Vol. 79, pp. 55-70 (2002)